The infection of macaques by simian immunodeficiency virus (SIV) results in many of the characteristics of HIV infection and progression to AIDS in humans, including loss of CD4+ T cells and susceptibility to opportunistic infections. Our studies have used this SIV macaque model to focus on various vaccine approaches. 1. Vaccinia virus recombinant vaccines. Our infectious and pathogenic molecular clone of SIV/Mne, obtained from a pig-tailed macaque with AIDS, has been used to construct various recombinant vaccinia viruses that express differing portions of the SIV virus. We previously reported that envelope (gp160)-based vaccines, when used in a recombinant vaccinia virus priming and subunit protein boosting regimen, protected all macaques from infection by the cloned homologous virus. The breadth of this immunity, however, appears to be limited, since approximately half of the immunized animals were infected after challenge by a heterologous SIV. To examine the role of core (gag/pol) antigens in inducing or broadening protective immunity, we immunized macaques with either gp160, core antigens, or both antigens formulated as a mixture. Animals immunized with core antigens alone were not protected even against the homologous virus challenge, although the virus load was 100-fold lower than that of control (non-immunized) animals, suggesting an important role for core antigen-specific immune responses in controlling the acute infection. Animals that received both envelope and core antigens were now protected against a heterologous virus challenge, indicating that responses to core antigens contributed to the broadening of protective immunity. Our results argue for the inclusion of multiple antigenic targets in the design of recombinant vaccines against AIDS. 2. Role of cellular antigens in AIDS vaccines. Macaques immunized with uninfected human cells have been shown to be protected from challenge with SIV propagated in human cells. Studies in which macaques were immunized with various cellular antigens and then challenged with SIV grown in the same cells from which the antigens were purified have identified HLA Class II DR 4 as one of the antigens responsible for this protection. Future studies in macaques will address whether the alpha- or the beta- chain of HLA DR is protective, and whether the protection extends to other DR molecules such as DR1. In addition to these xeno-immunizations studies, we are also pursuing similar studies in macaques to examine whether DR is also protective in an allo-immunization setting.